The hippocampus plays an important role in a number of normal physiological processes and in a variety of pathological conditions, including Alzheimer's disease and temporal lobe epilepsy. Development of a complete understanding of the molecular and cellular mechanisms involved in regulation of hippocampal function could lead to new strategies for treatment of these disorders. Until recently, it was thought that all of the actions of glutamate, the major excitatory neurotransmitter in the hippocampus, were mediated by activation of ligand-gated cation channels. However, it is now clear that glutamate also activates metabotropic glutamate receptors (mGluRs), that are coupled to effector systems through GTP binding proteins. mGluRs play a number of important roles in regulating cell excitability and synaptic transmission in the hippocampus. A complete understanding of both normal and pathological hippocampal function will require a detailed understanding of the roles of mGluRs in modulating hippocampal physiology and the molecular mechanisms involved in regulating signaling by members of this important receptor family. Eight m(GluR subtypes (mGluR1 - mGluR8) have been identified by molecular cloning. In the hippocampus, evidence suggests that m(GluR2, mGluR7 and mGluR8 are all localized on presynaptic glutamatergic nerve terminals where they may serve to inhibit glutamate release. However, the postulated roles of mGluR7 and mGluR8 in regulating transmission at specific hippocampal synapses have not been definitively established. We recently reported that mGluR- mediated regulation of glutamate release can be inhibited by activation of protein kinase C (PKC). However, at present, the mechanism by which PKC inhibits signaling by presynaptic mGluRs is not known. A series of studies is proposed in which a combination of anatomical, pharmacological, and genetic approaches will be used to rigorously test the hypothesis that mGluR7 and m(GluR8 serve as presynaptic receptors at two major hippocampal synapses. We will then employ biochemical, electrophysiological, and molecular approaches to rigorously test the hypothesis that activation of PKC inhibits the function of presynaptic mGluRs by directly phosphorylating the receptors and inhibiting receptor coupling to GTP binding proteins. These studies could lead to a fundamental advance in our understanding of the mechanisms involved in regulation hippocampal function and could have important implications regarding novel approaches to treatment of disorders involving pathological changes in the hippocampus.